Investigation of CFTR Function in Human Nasal Epithelial Cells Informs Personalized Medicine

Area of Science:

• Cell Biology
• Genetics
• Respiratory Medicine

Background:

• Cystic fibrosis (CF) is a genetic disorder caused by mutations in the CFTR gene.
• Personalized medicine approaches are crucial for optimizing treatment for CF patients with diverse CFTR variants.
• Human nasal epithelial (HNE) cells offer a valuable in vitro model for studying CFTR function and drug responses.

Purpose of the Study:

• To evaluate the clinical utility of HNE cells in assessing CFTR function.
• To determine the response of HNE cells with rare CFTR variants to CFTR modulators.
• To explore the potential of HNE functional studies as a diagnostic tool for mild CF.

Main Methods:

• HNE cells were isolated from 10 participants with rare CFTR variants.
• Cells were differentiated at the air-liquid interface and CFTR function was measured using Ussing chambers.
• CFTR function was assessed at baseline and in response to ivacaftor or elexacaftor/tezacaftor/ivacaftor (ETI).

Main Results:

• HNE cells from participants with Q359R and G480S variants showed increased CFTR function with modulators, correlating with clinical improvement.
• R334W variant HNEs demonstrated moderate responses to modulators, with one participant showing in vivo improvement.
• R560T variant HNEs showed no response, consistent with missplicing, while R117H;7T;TG10/5T;TG12 HNEs facilitated a mild CF diagnosis and responded to modulators.

Conclusions:

• HNE cell functional studies are versatile for guiding CFTR modulator therapy and predicting treatment outcomes.
• HNEs can accurately assess CFTR function in rare variants and inform personalized treatment strategies.
• HNE functional assays show promise as a clinical diagnostic test for identifying mild CF cases.